Di(2-ethylhexyl) phthalate induces a functional zinc deficiency during pregnancy and teratogenesis that is independent of peroxisome proliferator-activated receptor-alpha.
Di(2-ethylhexyl) phthalate (DEHP) is a peroxisome proliferator whose administration to rodents induces a pleiotropic response mediated by the peroxisome proliferator-activated receptor-alpha (PPAR alpha). The mechanisms underlying DEHP-induced reproductive toxicity and teratogenicity are not well understood but could be the result of an alteration in gene expression by PPAR alpha. Additionally, phthalate exposure is known to impair fetal zinc (Zn) levels during pregnancy. In this work, we investigated whether the reproductive toxicity and teratogenicity of DEHP are mediated by PPAR alpha and whether the receptor influences maternal and/or embryonic Zn metabolism. Pregnant female mice, homozygous wild-type (+/+) or PPAR alpha -null (-/-), were intubated with either vehicle alone or 1,000 mg DEHP/kg body weight on gestation day (GD) 8 and 9. Pregnancy outcome was evaluated on GD10 and GD18 in two cohorts of animals. Compared to controls, DEHP administration resulted in maternal toxicity, embryo/ fetal toxicity, and teratogenicity in both (+/+) and (-/-) mice. Maternal liver mRNA for cytochrome P-450 4A1 (CYP4A1) was higher in DEHP-treated (+/+) mice but not in DEHP-treated (-/-) mice on GD10, consistent with their respective phenotype. Maternal liver MT and Zn levels were significantly higher than in controls on GD10. In addition, embryonic Zn content was significantly lower in both genotypes treated with DEHP compared to controls. Results from this work show that DEHP-induced reproductive toxicity, teratogenicity, and altered Zn metabolism are not mediated through PPAR alpha-dependent mechanisms. In addition, this work suggests that DEHP-induced alterations in Zn metabolism contribute to the mechanisms underlying DEHP-induced reproductive toxicity and teratogenicity.
Peters
J M
JM
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. jpeters@helix.nih.gov
Taubeneck
M W
MW
Keen
C L
CL
Gonzalez
F J
FJ
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D004051:Diethylhexyl Phthalate / Q000633:toxicity*; D005260:Female; D005333:Fetus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000502:physiology*; D011247:Pregnancy; D011256:Pregnancy Outcome; D011270:Pregnancy, Animal / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D015032:Zinc / Q000172:deficiency*
D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D004051:Diethylhexyl Phthalate; D015032:Zinc